Visual impairment is a worldwide problem, with 314 million people visually impaired, of whom 45 million are blind. The leading causes of visual impairment are cataract, glaucoma, uncorrected refractive errors, diabetic retinopathy and age-related macular degeneration. This proposal will identify genetic components for two of these important ocular conditions: glaucoma and refractive error in the Beaver Dam Eye Study (BDES), a longitudinal population based cohort study of age related eye diseases. This study includes 4926 participants including 1948 individuals with DNA who are part of 601 families reconstructed from the population based study. It is an ideal population in which to identify genes which lead to the development of glaucoma and refractive errors. Elevated intraocular pressure (IOP) is a major risk factor for primary open-angle glaucoma that has been shown to have both genetic and environmental components. Our previous studies in the BDES population have demonstrated strong heritability for IOP (30-35%) suggesting a genetic component to this trait and demonstrated genome- wide significant evidence of linkage to chromosome 19. Refractive errors(Myopia and Hyperopia) are a common eye disorders and which lead to blurred vision and visual impairment if not corrected. The measured unit of refraction (spherical equivalent) is highly heritable (h2=68%) in the BDES cohort and genetic linkage analysis identified a region on chromosome 22 that demonstrated genomewide suggestive evidence of linkage to refraction and to myopia. We hypothesize that through next-generation sequencing we can identify the candidate genetic variants responsible for the linkage signals of both intraocular pressure (chromosome 19) and refractive errors (chromosome 22). Variants identified through these sequencing efforts will then be evaluated through association testing in the entire BDES population. Finally, detailed genotype-phenotype analysis will be conducted of disease-associated variants. Detection of genes that cause elevated intraocular pressure and refractive errors can be used to identify biological pathways that can be targeted with treatments to reduce the morbidity associated with these diseases. PUBLIC HEALTH RELEVANCE: Visual impairment is a worldwide problem, with 314 million people visually impaired, of whom 45 million are blind. The leading causes of visual impairment include glaucoma and uncorrected refractive errors. Genetic factors have been shown to important in controlling both of these ocular traits and our previous linkage analysis has provided evidence of a gene for intraocular pressure on chromosome 19 and a gene refraction on chromosome 22. We are proposing to identify the genes responsible for these linkage signals using next-generation sequencing on families with extreme values of these traits who participated in the Beaver Dam Eye Study.